From: Subject: ScienceDaily: Genetic Pathways To Curable And Incurable Forms Of Pancreatic Cancer Identified Date: Mon, 19 Mar 2007 11:21:47 -0400 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C76A18.C8142030" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3028 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C76A18.C8142030 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.sciencedaily.com/releases/2007/03/070312152236.htm ScienceDaily: Genetic Pathways To Curable And = Incurable Forms Of Pancreatic Cancer Identified

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Source:	Fred Hutchinson Cancer = Research=20 Center
Date:	March 13,=20 2007

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Cancer, Breast Cancer, Colon Cancer, Brain Tumor, Lung Cancer, Ovarian = Cancer

Genetic Pathways To Curable And Incurable Forms = Of=20 Pancreatic Cancer Identified

Science Daily =97 = Pancreatic=20 ductal adenocarcinoma is an almost uniformly fatal disease = regardless of=20 the stage at time of diagnosis. However, a small percentage of = patients=20 develop a form of ductal adenocarcinoma associated with cystic = lesions=20 that can be detected earlier, is less aggressive and has a 50 = percent=20 long-term survival rate. Why cystic ductal pancreatic cancer = behaves=20 differently, despite carrying the same basic genetic mutations as = the more=20 common and deadly type of ductal pancreatic cancer, has long been = a=20 mystery. Now researchers at Fred Hutchinson Cancer Research Center = have=20 unlocked the genetic reason why.

Using unique mouse models to mimic the progression of both = forms of=20 human pancreatic cancer, researchers have discovered that a = specific=20 sequence of otherwise common genetic mutations is responsible for = sending=20 cells down the less-traveled path toward cystic pancreatic cancer = versus=20 the well-traveled route to the more fatal form of ductal = pancreatic=20 cancer.

Sunil Hingorani, M.D., assistant member of the Hutchinson = Center's=20 Clinical Research and Public Health Sciences divisions, led a = study to be=20 published in the March 12 issue of the journal Cancer Cell that = explains=20 this sequence and details why the cells behave differently.

"Although at their end stage the two different routes to ductal = pancreatic cancer can look very much the same under the = microscope,=20 involve the same constellation of genetic events, and culminate in = invasive and metastatic disease that can ultimately kill patients, = one=20 route is 100 percent fatal while the other is 50 percent curable," = Hingorani said. "Until now we didn't understand why. What these = studies=20 suggest is that it's not just the total complement of mutations = that=20 determines the behavior of these cancers but also the sequence in = which=20 the mutations arise."

About 5 percent of all primary tumors of the pancreas, out of = 40,000=20 annual new cases in the United States, arise from cystic tumors. =

The findings reported in the journal by Hingorani and = colleagues=20 represent an accidental discovery. The researchers started out = studying=20 the common genetic pathways to pancreatic ductal adenocarcinoma in = hopes=20 of finding clues to developing early detection biomarkers and = possible=20 treatments to halt the progression of the disease. The work = involved=20 activating the pancreatic cancer oncogene called Kras and then = selectively=20 mutating tumor-suppressor genes such as p53, p16 and Dpc4 in = different=20 combinations.

In the mouse model, which Hingorani first developed while at = the=20 University of Pennsylvania, the combination of Kras and p53 led to = the=20 more deadly form of pancreatic ductal adenocarcinoma. Earlier = studies by=20 researchers in Boston also found the same association between Kras = and=20 p16. From studies of human cancers, it is known that mutations in = Dpc4 can=20 also occur, but they do so late in the course of disease = progression. The=20 current study showed that the combination of Kras and an early = mutation of=20 Dcp4, in which one copy of the suppressor gene is eliminated, lead = to=20 cancer by a different path, beginning with the creation of a = distinct=20 class of precancerous lesions in the ductal epithelium called = mucinous=20 cystic neoplasms (MCN). This initiates a process that results in = the rarer=20 but far less deadly cystic pancreatic cancer.

MCN lesions often are large enough to be detected early by MRI = or CT=20 scan and also to cause symptoms. The cells in this cancer also = react=20 differently to a key signaling protein, TGFb, which can induce = cancer=20 cells to change shape and become more mobile and invasive. It = turns out=20 that the cystic pancreatic cancer cells are resistant to these = effects of=20 TGFb and these types of cancers are also less likely to invade = surrounding=20 tissues and to metastasize, or spread, to other organs. These = properties=20 likely contribute to the improved survival seen with this form of = the=20 cancer, Hingorani said.

Conversely, the initial lesions that lead to the more common = and deadly=20 form of pancreatic ductal adenocarcinoma, called pancreatic = epithelial=20 neoplasms, are tiny enough to be undetectable until the disease = has=20 progressed to the point where survival is almost nil. Moreover, = these=20 cells appear to be highly sensitive to the tumor-promoting = properties of=20 TGFb and thereby manifest a more aggressive behavior.

"With accurate animal models of both forms of pancreatic ductal = cancers=20 now in hand, it should be possible to unravel the detailed = mechanisms=20 behind their distinct behavior and hopefully identify points of=20 vulnerability in the more fatal form to improve survival," = Hingorani said.=20

Research for this paper was supported by the National Cancer = Institute,=20 the National Institutes of Health, an American Academy of Cancer = Research=20 and PanCAN Career Development Award, and by the Canary Foundation. = Contributing to the research were scientists from the University = of=20 Washington School of Medicine in Seattle, Abramson Cancer Center = in=20 Philadelphia, Sol Goldman Cancer Research Center in Baltimore, = Harper=20 Hospital and Wayne State University School of Medicine in Detroit, = and the=20 National Institutes of Diabetes and Digestive and Kidney Diseases = in=20 Bethesda, Maryland.

Note: This story has been adapted from a news release = issued by=20 Fred Hutchinson Cancer Research Center.

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